PROJECT SUMMARY/ABSTRACT: Project 2 Cancer is one of the leading causes of human mortality worldwide. Owing to its highly heterogeneous nature, and evolutionary cell populations dynamics, it is also one of the most treatment-resistant diseases. Vast majority of cancer related deaths are due to invasive and ultimately metastatic spread of tumor cells. To target cancer metastasis, new insights are required from orthogonal perspectives. In Project #1, we propose to investigate the fundamental mechanisms responsible for initiation and progression of cancer metastasis with a focus on the cell-autonomous characteristics of cancer cells. In project #2 we propose to focus on non-cell- autonomous control of invasive process, i.e., those involving cell-cell interactions, both within invading tumors and at the tumor-stroma interface. Our preliminary data, as well as accumulating evidence from other labs indicate that cancer invasion is a collective cell behavior, involving a variety of cell-cell interactions that shape the possibility and extent of cancer progression. Importantly, many of the regulatory pathways and networks, and the associated phenotypes involved in invasion, are shared by normal physiological processes, including wound healing, placental implantation into endometrium, and blood vessel growth. In an innovative approach, we will capitalize on the differences between normal invasive processes in different species and corresponding differences in the aggressive cancer progression in the same species, to gain comparative evolution-based insights into factors promoting and arresting invasive spread. We will test these insights by focusing on hetero-typic interactions between cancer and stromal cells (Aim 1) and homo-typic interactions among cancer cells adopting different phenotypes (Aim 2). A key novel hypothesis that will be tested in this analysis is that cancer-stromal interactions can yield novel targets that are stromal-specific and, as such, will be less subject to development of drug resistance, if considered as a part of new therapeutic development. Furthermore, we hypothesize that disruption of interaction between aggressive, migratory cancer cells and their proliferative counterparts can decrease the degree and effect of invasive cancer spread. The results of this analysis are thus expected to lead to new approaches to controlling invasive cancer spread.